Tissue specific defects in insulin action or in metabolic pathways thought to be essential to maintaining glucose homeostasis do not always produce the expected outcome. For example, complete removal of either GLUT4 or insulin receptor in muscle does not exhibit a significant phenotype unless challenged by aging or high fat feeding. The failure to manifest marked hyperglycemia despite significant impairments in muscle glucose uptake suggests that other tissues compensate for the defect. The pancreas compensates by increasing insulin secretion and adipose tissue compensates by enhancing glucose uptake and lipid deposition or secreting a factors that modifies glucose metabolism in other tissues. Little or no work has addressed the role of the liver. The primary variables measured in vivo to detect changes in hepatic metabolism especially in mice are tracer determined glucose turnover and the ability of insulin to inhibit hepatic glucose production during a euglycemic hyperinsulinemic clamp. Interestingly in most cases it has been difficult to detect underlying defects in hepatic insulin action except when diabetes and the associated hyperglycemia are present. Our data indicate that the liver has the unique ability to adapt to a sustained increase in glucose availability by enhancing its capacity to take up glucose. Moreover, while the liver initially stores the glucose as glycogen, as the duration of high glucose exposure increases a large fraction of the glucose is released as lactate which is subsequently removed by peripheral tissues. The euglycemic hyperinsulinemic clamp, while effective in detecting alterations in peripheral glucose uptake, cannot be used to discriminate between changes in peripheral and liver glucose uptake. To directly assess liver glucose uptake requires arterio-venous difference techniques that, while readily available in large animal models, cannot be implanted in conscious mice. Consequently very little work in mouse models has examined how liver glucose uptake is regulated and how the liver adapts to impairments in peripheral insulin action and glucose disposal. The Mouse Metabolic Phenotyping Center (MMPC) here at Vanderbilt has developed surgical approaches that will allow us for the first time to study the adaptive response of the liver in a conscious mouse. We will combine novel tracer methodology with a chronically catheterized conscious mouse model to quantify the adaptive response of the liver and then test this adaptive response in mouse models of insulin resistance.